The overall goal of this revised competing renewal application remains to carefully define the utility of PET in the management of patients with breast cancer. In the initial funding period we made progress toward this goal, demonstrating that PET appears promising in chemotherapy monitoring, staging for regional metastases, and in detecting primary tumors in radiographically-dense breasts. We also recently described a consistent molecular alteration in breast cancers versus normal breasts, overexpression of the GLUT-1 glucose transporter by the cancers, and showed (in rodent breast cancer) that FDG uptake in the tumors is significantly- correlated with the expression of this marker on viable cancer cells. In this revised renewal application we will build upon our experience addressing the following clinically important questions: 1) Can PET reliably predict the outcome of chemotherapy? Specifically a) can FDG-PET scans after 1 or two cycles of chemotherapy reliably identify women who are destined to subsequently fail non-marrow ablative chemotherapy, thus identifying women whose treatment should be changed to a non-cross reactive salvage regimen? and b) Can FDG-PET identify during the early induction period of treatment (before bone marrow transplant), the women who will benefit most (and least) from bone marrow transplantation? 2) Are PET scan findings at the time of diagnosis predictive of long-term outcome? Patients studied in the axillary node staging and chemotherapy protocols in the initial funding period will be followed for recurrence/death to help ascertain the predictive value of PET. 3) What are the histological correlates of the signal observed by PET scanning before and after cancer treatment? Correlative studies with biopsy samples from patients and in a rat model of breast cancer will be performed. Autoradiographic studies from the animal model of breast cancer will allow us to determine whether FDG is a reliable marker of viable GLUT- 1 positive tumor cell number after chemo or radiotherapy, or if significant tracer uptake is into reactive non-tumor elements. 4) Does 3D FDG-PET offer advantages over the standard 2D methods used to date in detecting axillary lymph node metastases or primary breast cancers? Pilot studies will be performed evaluating primary lesions and axillary nodal imaging to determine if more comprehensive studies should be pursued with the 3D method. The studies we propose will allow us to better define the role of FDG PET in patients with breast cancer and answer basic questions regarding the FDG signal. The results in the breast cancer model should be applicable to FDG PET of other cancers.